Researchers at Virginia Commonwealth University's Massey Cancer Center have created a new method to improve the antileukemic activity of a novel agent that triggers programmed cell death, a development that could lead to more effective strategies for fighting leukemia and other malignancies.
The cell death process, or apoptosis, is characteristically impaired in cancer cells. The process is regulated by a large family of proteins that either promotes or inhibits cell death. Recently, considerable attention has focused on the development of agents that inhibit the actions of antiapoptotic members of this family.
One such agent, known as ABT-737, potently blocks the pro-survival effects of two proteins, Bcl-2 and Bcl-xL, according to Steven Grant, M.D., Massey's associate director for translational research and co-leader of the cancer center's cancer cell biology program. Grant is senior author of the study, which is published in the Jan. 15 issue of the journal Cancer Research.
In laboratory experiments, ABT-737 has been shown to be very effective in killing tumor cells. However, this agent is unable to block the actions of another anti-apoptotic family member, Mcl-1, and it has been found that increased expression of Mcl-1 in tumor cells significantly reduces the anti-tumor effectiveness of ABT-737.
Grant and colleagues demonstrated that interventions that reduce levels of Mcl-1 in leukemia cells dramatically increase the effectiveness of ABT-737. Specifically, they employed an agent called roscovitine to block the synthesis of Mcl-1 at the RNA level. Grant said that because Mcl-1 is a very short-lived protein, disrupting its synthesis rapidly lowers Mcl-1 levels.
Grant's team found that the simultaneous reduction in Mcl-1 expression in conjunction with disruption of the anti-apoptotic actions of Bcl-2 and Bcl-xL by ABT-737 resulted in the marked activation of an important pro-apoptotic protein known as Bak. Grant said that when Bak is freed from its constraints by these actions, it cooperates with other pro-death proteins to induce mitochondrial damage, culminating in the dramatic onset of apoptosis.
"Our findings are significant because we were able to employ pharmacologic agents to recapitulate the death process that occurs in normal cells, and which is impaired in their neoplastic counterparts," said Grant. "These findings could also have significant translational implications for the treatment of leukemia and potentially other malignancies."
"For example, analogs of roscovitine have recently entered the clinic, and a number of other agents capable of reducing Mcl-1 levels in tumor cells are currently being developed," he said.
Based upon the findings of Grant's group, regimens combining such agents with Bcl-2 antagonists like ABT-737 could represent a particularly effective treatment strategy in leukemia and various other malignancies.
This work was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society of America, and the Department of Defense.
Grant, a professor of medicine and the Shirley Carter and Sture Gordon Olsson Professor of oncology, worked with a team that included: Shuang Chen, Ph.D., Yun Dai, Ph.D., and Hisashi Harada, M.D., Ph.D., all in the VCU Department of Medicine; and Paul Dent, Ph.D., a professor in the VCU Department of Biochemistry.
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